Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration
Open accessAbstract
Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteria-derived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neuron degeneration, the wobbler mouse, where we preliminarily confirmed a protective effect of TLR4 antagonism. Compared with vehicle- and riluzole-treated mice, those chronically treated with VB3323 showed a decrease in microglial activation and morphological alterations of spinal cord neurons and a better performance in the paw abnormality and grip-strength tests. Taken together, our data add new understanding of the role of TLR4 in mediating neurotoxicity in the spinal cord and suggest that TLR4 antagonists could be considered in future studies as candidate protective agents for motor neurons in degenerative diseases.
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TLR4 deficiency or antagonist treatment extended life expectancy in hSOD1 G93A mice.
“TLR4 deficiency or antagonist treatment decreased microglia activation, improved motor function and extended life expectancy.309,310”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [310]
TLR4 deficiency or antagonist treatment improved motor function in hSOD1 G93A mice.
“TLR4 deficiency or antagonist treatment decreased microglia activation, improved motor function and extended life expectancy.309,310”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [310]
In the hSOD1 G93A transgenic mouse model, TLR4 expression was upregulated in microglia and astrocytes.
“In the hSOD1 G93A transgenic mouse model, the expression of TLR4 was upregulated in microglia and astrocytes”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [310]
TLR4 deficiency or antagonist treatment decreased microglia activation in hSOD1 G93A mice.
“TLR4 deficiency or antagonist treatment decreased microglia activation, improved motor function and extended life expectancy.309,310”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [310]
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- Authors
- De Paola, M., Mariani, A., Bigini, P., Peviani, M., Ferrara, G., Molteni, M., Gemma, S., Veglianese, P., Castellaneta, V., Boldrin, V., Rossetti, C., Chiabrando, C., Forloni, G., Mennini, T., & Fanelli, R.
- Affiliations
- Mario Negri Institute for Pharmacological Research (IT)
- University of Insubria (IT)
- ORCID
- Venue
- Molecular Medicine
- Published
- 2012-05-01
- Volume
- 18
- Issue
- 6
- Pages
- 971-981
- ISSN
- 1076-1551 (ISSN-L)
- 1528-3658
- PMC
- PMC3459480
- OpenAlex
- W197102779
- Cited by
- 75
- References
- 53
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 3 · 2020: 10 · 2019: 5 · 2018: 9 · 2017: 8 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 3
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- creativecommons.org/licenses/by/4.0 (tdm)
- Locations
- Molecular Medicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IrInSubria (University of Insubria) (submittedVersion)
- Funders
- Fondazione Cariplo (2009-2426)
- Regione Lombardia
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR4, TLR4 antagonism, motor neuron degeneration, neuroinflammation, microglial activation, lipopolysaccharide, inflammatory cytokines, neuroprotection, wobbler mouse, spinal cord, neurodegenerative diseases, riluzole
- MeSH terms
- Animals, Cell Survival, Disease Models, Animal, Ligands, Lipopolysaccharides, Mice, Inbred C57BL, Mice, Neurologic Mutants, Motor Neurons, Muscles, Nerve Degeneration, Neurotoxins, Spinal Cord, Tumor Necrosis Factor-alpha, Microglia, Neuroprotective Agents, Cell Culture Techniques, Cell Shape, Toll-Like Receptor 4, Mice
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